The long term goal is to understand the phenomenon of Plasmodium antigenic variation, a major factor in the development of chronic malaria blood-stage infections and a determinant of parasite virulence. The proposed studies will be performed using the Plasmodium knowlesi/rheusus monkey model system, in which malaria antigenic variation was first identified. The P. knowlesi variant antigens are high molecular weight, parasite-encoded proteins that are inserted into the infected host erythrocyte membrane and are partially exposed at its surface. These proteins, known as the SICA (schizont infected cell agglutination) antigens, change in size and antigenicity int he course of a blood infection. With the recent cloning of the first variant antigen genes of P. knowlesi (the SICA var genes), which are members of a large multigene family, it is now possible to study the mechanisms of antigenic variation in vivo as well as in-vitro. Previous in-vivo studies using unique, stable cloned populations of P. knowlesi, which express known variant antigen phenotypes, and the rhesus monkey model system have suggested that antigenic variation of the SICA var proteins is induced by variant-specific antibody, is modulated by athe host spleen, and is a factor in the virulence of this parasite. Now with molecular probes in-hand, questions pertaining to tahe molecular mechanisms of gene expression and the immunobiology of antigenic variation can be addressed. Importantly, athe studies that are possible with P. knowlesi will provide information about the process of malaria antigenic variation that may not be generated by direct studies of the predominant human malarias P. falciparum or P. vivax, since there are neither comparable in- vivo models nor in-vitro systems that are easily manipulated and controlled. Thus, the proposed work provides a valuable interspecies comparative model that will in all likelihood continue to generate knowledge that is relevant for and contribute to understanding antigenic variation of human malaria parasites. Although the function of related P. falciparum variant antigens is currently believed to be cytoadherence/sequestration, it is also important to ask what other functions these proteins may have, as neither P. knowlesi nor P. vivax show a comparably marked sequestration as seen in falciparum malaria. Determining the genetic and immunobiological mechanisms involved with switching of malaria variant antigen phenotypes will be of general importance for furthering the knowledge about molecular mechanisms of parasitism in malaria and the P. knowlesi model could provide athe critical clues necessary for deciphering these mechanisms.